The goal of this proposal is to develop effective methods of treating infants and children with inborn errors of ureagenesis. We propose to fulfill this goal by: 1) maintaining a national referral center to coordinate the therapeutic protocol, 2) develop a dietary nitrogen intake that will minimize the requirement for waste nitrogen excretion and activate metabolic pathways that enhance waste nitrogen excretion. These pathways include the biosynthesis and excretion of citrulline and argininosuccinic acid in argininosuccinate synthetase and lyase deficiency respectively and hippurate and phenylacetylglutamine in deficiencies of carbamyl phosphate synthetase, ornithine transcarbamylase and arginionosuccinate synthetase. 3) Improve methods of treatment of intercurrent hyperammonemic episodes by similar techniques with efforts to increase the rate of hippurate synthesis. In-vivo residual enzyme activities of patients with these diseases will be examined by studying 15NH4 enrichment of urea. This therapy will be extended to other diseases (Reye's syndrome, portalsystemic encephalopathy, organic acidemias) where hyperammonemia may have a role. It is also planned to perform a study in rats to evaluate the in vivo rate limiting steps of hippurate synthesis. The long term neurodevelopmental consequences of low grade neonatal hyperammonemia in low birth weight children will be studied by developmental and psychological methods.